Direct-acting oral anticoagulants (DOACs): increased risk of recurrent thrombotic events in patients with antiphospholipid syndrome

A clinical trial has shown an increased risk of recurrent thrombotic events associated with rivaroxaban compared with warfarin, in patients with antiphospholipid syndrome and a history of thrombosis. Other direct-acting oral anticoagulants (DOACs) may be associated with a similarly increased risk.

Advice for healthcare professionals:

  • direct-acting oral anticoagulants (DOACs) are not recommended in patients with antiphospholipid syndrome, particularly high-risk patients (those who test positive for all 3 antiphospholipid tests — lupus anticoagulant, anticardiolipin antibodies, and anti-beta 2 glycoprotein I antibodies)
  • review whether continued treatment with a DOAC is appropriate for patients diagnosed with antiphospholipid syndrome, particularly high-risk patients, and consider switching to a vitamin K antagonist such as warfarin
  • report suspected adverse drug reactions to DOACs on a Yellow Card, including any thromboembolic events suspected to be due to lack of efficacy

Risk of recurrent thrombotic events in patients with antiphospholipid syndrome

Direct-acting oral anticoagulants (DOACs) are indicated for a variety of uses related to anticoagulation (see full indication in background). DOACs available are apixaban (Eliquis), dabigatran etexilate (Pradaxa), edoxaban (Lixiana▼), and rivaroxaban (Xarelto▼).

An EU review has concluded that use of DOACs in patients with antiphospholipid syndrome could be associated with increased rates of recurrent thrombotic events compared with therapy with a vitamin K antagonist.

The level of evidence for an increased risk of recurrent thrombotic events in patients with antiphospholipid syndrome differs among DOACs (see below for information for each medicine). However, there is not enough evidence that any DOAC offers sufficient protection in patients diagnosed with established antiphospholipid syndrome, particularly in patients at the highest risk for thromboembolic events (those who test positive for all 3 antiphospholipid tests – lupus anticoagulant, anticardiolipin antibodies, and anti-beta 2 glycoprotein I antibodies). Changes are therefore being made to the product information for these medicines to advise that use of DOACs in these patients with antiphospholipid syndrome is not recommended.

Rivaroxaban

The TRAPS study1 was an investigator-sponsored, randomised, open-label, multicentre study with blinded endpoint adjudication (clinicaltrials.gov NCT02157272). Outcomes with rivaroxaban were compared with warfarin in patients with antiphospholipid syndrome and a history of thrombosis, and at high risk for thromboembolic events (patients who persistently tested positive for all 3 antiphospholipid tests).

The trial was terminated prematurely after the enrolment of 120 patients due to an excess of thromboembolic events among patients in the rivaroxaban arm.1 Mean follow-up was 569 days. In the study, 59 patients were randomly assigned to rivaroxaban 20 mg (15 mg dose for patients with creatinine clearance <50 ml/min) and 61 to warfarin (INR 2.0–3.0).

Thromboembolic events occurred in 12% of patients assigned to receive rivaroxaban (4 cases of ischaemic stroke and 3 of myocardial infarction). No thromboembolic events were reported in patients assigned to receive warfarin. Major bleeding events occurred in 4 patients (7%) in the rivaroxaban group and 2 patients (3%) in the warfarin group. No deaths were reported.

Apixaban, edoxaban and dabigatran etexilate

Available data for apixaban, edoxaban and dabigatran etexilate are more limited than for rivaroxaban because there have been no completed clinical trials of these products in patients with antiphospholipid syndrome. However, available data suggest these other DOACs may be associated with a similarly increased risk of recurrent thrombotic events as with use of rivaroxaban.

One investigator-sponsored research study is ongoing to study rates of thrombosis in patients with antiphospholipid syndrome on apixaban (ASTRO-APS; Clinicaltrials.gov identifier NCT02295475). The final results are not yet available.

Background

DOACs are approved for the treatment and prevention of venous thromboembolism (VTE) and prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation with one or more risk factors. Apixaban, dabigatran etexilate, and rivaroxaban are also approved for prevention of VTE in conjunction with hip or knee replacement surgery.

Rivaroxaban is also approved, in addition to acetylsalicylic acid (aspirin), for the prevention of atherothrombotic events in patients with coronary artery disease or symptomatic peripheral artery disease at high risk of ischaemic events, and in addition to acetylsalicylic acid or acetylsalicylic acid plus clopidogrel or ticlopidine, in patients after an acute coronary syndrome event with elevated cardiac biomarkers.

Report suspected adverse drug reactions with DOACs

Rivaroxaban (Xarelto▼) and edoxaban (Lixiana ▼) are subject to additional monitoring, and so any suspected adverse drug reactions should be reported to the Yellow Card Scheme. For all DOACs, serious suspected adverse drug reactions, including any cases of thromboembolic events due to lack of efficacy, should be reported on a Yellow Card. Every Yellow Card report counts, and few minutes taken by you or your patient to report can make a lifetime of difference for others – so don’t delay, report today!

Further information

PRAC recommendations on signals adopted at April 2019 meeting.

Letter sent to healthcare professionals. May 2019.

Published 19 June 2019